The corneal epithelium is one of the most sensitive and critical structures of the eye. It is affected in nearly every disease of the ocular surface, ranging from corneal abrasions and dry eyes to severe corneal melts and infections. Currently, there are very limited treatments that can specifically enhance the corneal epithelial function. In particular, there are no pharmacologic approaches to promote epithelial repair in patients with a compromised corneal epithelial barrier. The long term objective of this research application is to contribute to the development of novel and innovative treatments for patients with visually disabling ocular surface diseases by defining the mechanisms of epithelial barrier disease and repair. Our preliminary studies provide strong evidence that Notch1 plays a key role in regulating the corneal epithelial barrier repair and thus Notch1-/- mice provide a unique model for studying corneal epithelial barrier disease. To accomplish the research objectives of this application, the following two specific aims will be pursued: (1) Characterize the epithelial barrir function and the cell-cell adhesion defect using mice with conditional loss of Notch1 as a model, (2) Elucidate the inflammatory signaling pathways that are activated during epithelial injury/repair and determine their role in the development of inflammation and metaplasia using Notch1-/- mice as a model. These results will provide critical information for the development of therapies for patients with visually disabling ocular surface disorders. We will identify a number of candidate pathways and drugs for clinically enhancing the function of the corneal epithelium and suppressing corneal inflammation.